Vasoprotection by Caloric Restriction Mimetics in Aging

衰老过程中热量限制模拟物的血管保护作用

• 批准号: 8320900
• 负责人: Anna Csiszar
• 金额: $ 17.28万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8320900
• 关键词: Address; Age; Aging; Alzheimer' s Disease; Animal Feed; Animals; Antioxidants; Aorta; Apoptosis; Apoptotic; Arteries; Attention; Attenuated; Behavioral; Blood; Blood Vessels; Blood capillaries; Blood flow; Brain; Caloric Restriction; Carbon Dioxide; Cells; Cerebrovascular Circulation; Cerebrum; Characteristics; Cognitive; Complex; Data; Dementia; Diet; Disease; Drug Metabolic Detoxication; Elderly; Endothelial Cells; Exhibits; Free Radicals; Functional disorder; Genes; Genetic; Goals; Healthcare Systems; Hippocampus (Brain); Homeostasis; Hypoxia; Impaired cognition; Impairment; Inflammation; Injury; Intervention; K-Series Research Career Programs; Learning; Liver; Longevity; Mammals; Mediating; Mediation; Medical; Memory; Metabolic; Modeling; Molecular Target; Mus; NF-E2-related factor 2; Names; Neurocognitive; Neurons; Oklahoma; Organ; Oxidation-Reduction; Oxidative Stress; Pathologic Processes; Pathway interactions; Performance; Phenotype; Physiology; Play; Production; Proteins; Publishing; Quality of life; Regimen; Regional Blood Flow; Regulation; Resistance; Resveratrol; Risk; Role; Role Concepts; Seminal; Serum; Societies; Stroke; Structure; Sulforaphane; System; Testing; Training; Tube; Up-Regulation; Vascular System; Vascular blood supply; Wild Type Mouse; age related; aged; aging brain; angiogenesis; capillary; cerebrovascular; cognitive function; density; design; dietary restriction; feeding; improved; middle age; migration; mimetics; novel; novel strategies; older patient; prevent; protective effect; public health relevance; transcription factor; tumorigenesis

DESCRIPTION (provided by applicant): This is Beeson Career Development Award application designed to provide Dr. Anna Csiszar with additional training related to neurocognitive function at the Reynolds Oklahoma Center on Aging. Dr. Csiszar is an outstanding, well published candidate and the additional training will provide expertise in behavioral analyses, neurostereology, and cerebrovascular analyses necessary for her to achieve independence. Cognitive function decreases with age even in the absence of overt pathological processes. This decline in cognitive function clearly diminishes quality of life, is a major factor in loss of independence, and imparts a costly burden to society as a whole and to the medical health care system in particular. Previous studies demonstrated that age-related cerebrovascular rarefaction and microvascular dysfunction impair hippocampal blood flow, which has an etiologic role in cognitive decline during aging. The goal of this proposal is to identify key cellular mechanisms that can be targeted therapeutically to prevent/reverse age-related cerebral microvascular alterations maintaining normal hippocampal blood flow and protecting neurocognitive function. The direction and hypotheses of this application emerge from key findings that caloric restriction (CR) and the CR mimetic resveratrol have the potential to beneficially impact vascular physiology in aged mammals. We propose to test the hypothesis that caloric restriction protects the cerebral microvasculature from the deleterious effects of oxidative stress associated with aging, via induction of the Nrf2/ARE- regulated ROS detoxification systems. We posit that pharmacological activation of this pathway in endothelial cells (with resveratrol or sulforaphane) mimics the effects of caloric restriction, which contribute significantly to an intervention strategy for protection of neurocognitive function during aging. The following aims are proposed: 1) Assess whether CR and CR mimetics can delay/prevent the age-associated decline in cerebral regional blood flow, the reduction in capillary and arteriolar density and angiogenesis, and the decline in spatial learning and memory and determine whether genetic depletion of Nrf2 abrogates the microvascular protective effects of CR and resveratrol treatment. 2) Determine whether CR and CR mimetics can delay/prevent age-associated microvascular oxidative stress and impairment of local vasoregulatory mechanisms via induction of Nrf2/ARE-dependent antioxidant systems. 3) Determine whether systemic factors induced by CR in aged animals confer anti-oxidative, anti-apoptotic and pro-angiogenic effects on cerebral microvascular endothelial cells. Cultured endothelial cells will be treated with sera from ad libitum or CR fed animals and cellular ROS production, angiogenic potential and resistance to oxidative stress-induced apoptosis will be assessed. The role of Nrf2 activation in the protective effects of CR sera treatment will be elucidated. The proposed studies will provide the first comprehensive analysis of the role of the Nrf2/ARE pathway in maintaining a youthful cerebral microvascular phenotype during CR and will provide novel and definitive information on novel approaches to prevent/reverse cerebrovascular dysfunction and functional changes in the brain with age that are precursors to age-related disease, loss of cognitive function and the increased risk of dementia. PUBLIC HEALTH RELEVANCE: A decline in cognitive function clearly diminishes quality of life, is a major factor in loss of independence, and imparts a costly burden to society as a whole and to the medical health care system in particular. The age-related impairment of cerebral blood supply significantly contributes to cognitive decline in the elderly. The goal of this project is to identify novel molecular targets that can be activated pharmacologically to protect the cerebral blood vessels from free radical mediated injury and thus to improve cerebral blood flow and cognitive function in elderly patients. We will test the hypotheses that in the vascular system a protein named Nrf2 mediates multifaceted vasoprotective effects. We posit that treatment with Nrf2-activating molecules, or inducing Nrf2 by dietary restriction can exert significant cerebral vasoprotective effects protecting cognitive function in aged mice.

描述（由申请人提供）：这是Beeson职业发展奖申请，旨在为Anna Csiszar博士提供与俄克拉荷马州俄克拉荷马州衰老中心的神经认知功能有关的其他培训。 CSISZAR博士是一位出色的，出色的候选人，额外的培训将在行为分析，神经病学和脑血管分析方面提供专业知识，以实现独立性。即使在没有明显的病理过程的情况下，认知功能也随着年龄的增长而降低。认知功能的这种下降显然会降低生活质量，是失去独立性的主要因素，并给整个社会和医疗保健系统带来了昂贵的负担。先前的研究表明，与年龄相关的脑血管稀疏性和微血管功能障碍会损害海马血流，这在衰老期间在认知能力下降中具有病因。该提案的目的是确定可以针对治疗的关键细胞机制，以防止/反向年龄相关的脑微血管改变，以维持正常的海马血流并保护神经认知功能。这项应用的方向和假设来自关键发现，即热限制（CR）和CR模拟白藜芦醇具有对老年哺乳动物的血管生理的有益影响。我们建议通过诱导NRF2/areAs-nea-ear-nea-ear-new ros ros解毒系统来测试热量限制保护脑微脉管造成与衰老相关的有害作用的假设。我们认为，该途径在内皮细胞（使用白藜芦醇或硫烷）中的药理激活模仿热量限制的影响，这对保护神经认知功能的干预策略产生了显着贡献。提出了以下目的：1）评估CR和CR模拟物是否可以延迟/防止与年龄相关的大脑区域血流的下降，毛细血管和小动脉密度和血管生成的降低以及空间学习和记忆的下降，并确定NRF2的遗传损害是否会减少Cr cr cr cr的遗传效应和Resverrol效应。 2）确定CR和CR Mimetics是否可以通过诱导NRF2/诱导NRF2/是依赖性的抗氧化剂系统来延迟/预防与年龄相关的微血管氧化应激以及局部血管调节机制的损害。 3）确定CR在老年动物中诱导的系统因素是否允许抗氧化，抗凋亡和促血管生成对脑微血管内皮细胞。将评估培养的内皮细胞和CR喂养动物的血清以及细胞ROS的产生，血管生成潜力和对氧化应激诱导的凋亡的抗性。 NRF2激活在CR Sera处理的保护作用中的作用将得到阐明。拟议的研究将对NRF2/是维持CR的年轻脑微血管表型的途径进行首次全面分析，并将在预防/反向大脑功能变化的新颖方法上提供新颖和确定的信息，这些方法与大脑的功能变化有关，这是对年龄增长的疾病，损害疾病的损害，并增加了疾病的疾病，并增加了疾病的疾病，并增加了疾病的疾病，并增加了疾病的影响。 公共卫生相关性：认知功能的下降显然会降低生活质量，是失去独立性的主要因素，并赋予整个社会，尤其是医疗保健系统的昂贵负担。与年龄相关的脑血液供应损害显着导致老年人认知能力下降。该项目的目的是确定可以在药理上激活的新型分子靶标，以保护脑血管免受自由基介导的损伤，从而改善老年患者的脑血流和认知功能。我们将测试在血管系统中，一种名为NRF2的蛋白质介导多面血管保护作用的假设。我们认为，用NRF2激活分子进行治疗，或者通过饮食限制诱导NRF2可以发挥明显的脑干保护作用，以保护老年小鼠的认知功能。